University of Virginia Health System

Understanding how chromatin structure influences DNA-mediated processes has become a fundamental problem in cellular biology. Chromatin is known to influence the regulation of eukaryotic gene expression, DNA replication, DNA repair, and recombination. Abnormal chromatin structure can therefore deregulate these processes, which often leads to cellular transformation and ultimately tumorigenesis. Chromatin effects on gene expression can be either local (gene-specific) or global (non-specific). A classic example of a global chromatin effect is silencing, which is the epigenetic transcriptional repression of a large chromosomal locus, a phenomenon also called position effect. There is a specialized chromatin structure associated with these domains that prevents transcription of genes located either within or adjacent to these heterochromatin regions. The powerful genetic techniques available in the yeast Saccharomyces cerevisiae have led to its use as a model organism for studying silencing. The classic examples of silencing in yeast are repression of the HML and HMR mating-type loci and telomeres, which are the heterochromatin equivalents in yeast. These forms of silencing depend on a series of shared trans-acting factors that includes the products of the silent information regulator (SIR) genes. Among the four SIR genes, SIR2 is unique in that it is evolutionarily conserved from bacteria all the way up to humans, implying that it has an important and basic cellular function. The research in our lab is mainly focused on a recently identified form of silencing in yeast called rDNA silencing, which is the transcriptional repression of reporter genes located in the ribosomal DNA. There is a specialized Sir2p-dependent chromatin structure associated with the rDNA that is responsible not only for silencing reporter genes, but also for suppressing recombination between rDNA repeats. We are using genetic and biochemical approaches aimed at 1) identifying structural and regulatory genes associated with rDNA silencing, 2) determining the molecular mechanism of SIR-mediated gene silencing, and 3) investigating the role of rDNA silencing in other cellular processes. Preliminary work from our lab and others already suggests that rDNA silencing has effects on rRNA transcription, regulation of telomeric silencing, and cellular aging. rDNA silencing is unique in that the SIR3 and SIR4 genes are not required, suggesting that a separate Sir2p-associated complex may function at the rDNA. Given the evolutionary conservation of SIR2, exploiting rDNA silencing as a model for SIR2-mediated gene silencing is likely to be applicable to the chromosomal biology of higher eukaryotes, including humans.

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